The myelin-associated glycoprotein (MAG) is localized in the periaxonal membranes of PNS and CNS myelin sheaths where it appears to be involved in glia-axon interactions. Structural information about MAG obtained from sequencing of cDNA clones indicates that it has a single transmembrane domain separating two different developmentally regulated C-terminal tails generated by altenative splicing of the primary mRNA transcript from a heavily glycosylated N-terminus containing five domains that are related in sequence to each other and to molecules in the immunoglobulin gene superfamily such as neural cell adhesion molecule. In the dysmyelinating shaking dog mutant, the combined amount of proteolipid protein (PLP) and the related DM-20 protein are reduced to less than 2% of the control level and are disproportionally expressed in comparison to controls, suggesting that the PLP gene is the site of the primary genetic lesion in this X-linked mutation. In multiple sclerosis, MAG is reduced more than PLP or myelin basic protein in periplaque areas, and in many lesions much of the MAG is in the form of its proteolytic derivative, dMAG. Further studies on human IgM paraproteins associated with neuropathy revealed idiotypic heterogeneity among the antibodies from different patients with regard to their binding to sulfate-3- glucuronyl paragloboside and MAG. Injection of cat nerves with fresh sera from these patients supplemented with complement caused extensive demyelination adding to the evidence that the anti- MAG antibodies cause the neuropathy in these patients. A high proportion of patients with IgM gammopathy and neuropathy have paraproteins that react with various gangliosides, indicating that acidic glycolipid antigens are common in this type of neuropathy. High levels of antibodies to various gangliosides were found in about 15% of patients with Guillain-Barre syndrome and chronic demyelinating inflammatory polyneuropathy, a frequency significantly higher than in normal or other neurological disease controls.